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2.
Clin Immunol ; 237: 108963, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35259543

RESUMEN

Convalescent coronavirus disease 2019 (COVID-19) subjects who receive BNT162b2 develop robust antibody responses against SARS-CoV-2. However, our understanding of the clonal B cell response pre- and post-vaccination in such individuals is limited. Here we characterized B cell phenotypes and the BCR repertoire after BNT162b2 immunization in two convalescent COVID-19 subjects. BNT162b2 stimulated many B cell clones that were under-represented during SARS-CoV-2 infection. In addition, the vaccine generated B cell clusters with >65% similarity in CDR3 VH and VL region consensus sequences both within and between subjects. This result suggests that the CDR3 region plays a dominant role adjacent to heavy and light chain V/J pairing in the recognition of the SARS-CoV-2 spike protein. Antigen-specific B cell populations with homology to published SARS-CoV-2 antibody sequences from the CoV-AbDab database were observed in both subjects. These results point towards the development of convergent antibody responses against the virus in different individuals.


Asunto(s)
Anticuerpos Antivirales , Vacuna BNT162 , COVID-19 , Regiones Determinantes de Complementariedad , Anticuerpos Antivirales/inmunología , Formación de Anticuerpos , Vacuna BNT162/inmunología , COVID-19/inmunología , COVID-19/prevención & control , Regiones Determinantes de Complementariedad/genética , Humanos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/inmunología
3.
Am J Physiol Heart Circ Physiol ; 303(10): H1263-72, 2012 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-22982779

RESUMEN

Transient activation of p38 through anisomycin is demonstrated to precondition the heart against myocardial injury. However, it remains unknown whether specific TNF-α receptor (TNFR) p55/p75 and Nox2, a subunit of NADPH oxidase, are involved in this event. We sought to investigate whether the genetic disruption of TNFRp55/p75 and Nox2 eliminated cardioprotection elicited by anisomycin and whether p38-dependent activation of Nox2 stimulated TNFR to ultimately achieve protective effects. Adult wild-type and TNFR p55/p75(-/-) and Nox2(-/-) mice received intraperitoneal injections of anisomycin (0.1 mg/kg), a potent activator of p38. The hearts were subjected to 30 min myocardial ischemia/30 min reperfusion in the Langendorff perfused heart after 24 h. Left ventricular function was measured, and infarct size was determined. Myocardial TNF-α protein, Nox2, and superoxides releases were detected. Gel kinase assay was employed to detect the effect of p38 on Nox2 phosphorylation. Activation of p38 through anisomycin produces marked improvements in left ventricular functional recovery, and the reduction of myocardial infarction, which were abrogated by disruption of Nox2 and TNFR p55/p75. Disruption of Nox2 and TNFR p55/p75 abolished the effect of anisomycin-induced reduction of infarct size. Anisomycin induced the production of TNF-α, which was abrogated in Nox2(-/-) mice and by treatment with SB203580, but not by disruption of p55/p75. Anisomycin treatment resulted in an increase in Nox2 protein and the phosphorylation of Nox2, which was blocked by inhibition of p38. Taken together, these results indicate that stimulation of the Nox2 and TNFR p55/p75 pathway is a novel approach to anisomycin-induced cardioprotection.


Asunto(s)
Anisomicina/farmacología , Activadores de Enzimas/farmacología , Glicoproteínas de Membrana/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Miocardio/metabolismo , NADPH Oxidasas/metabolismo , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Animales , Anisomicina/administración & dosificación , Modelos Animales de Enfermedad , Activación Enzimática , Activadores de Enzimas/administración & dosificación , Inyecciones Intraperitoneales , Masculino , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/patología , NADPH Oxidasa 2 , NADPH Oxidasas/deficiencia , NADPH Oxidasas/genética , Inhibidores de Proteínas Quinasas/farmacología , Receptores Tipo I de Factores de Necrosis Tumoral/deficiencia , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo II del Factor de Necrosis Tumoral/deficiencia , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Transducción de Señal/efectos de los fármacos , Superóxidos/metabolismo , Factores de Tiempo , Factor de Necrosis Tumoral alfa/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
4.
Biochim Biophys Acta ; 1803(7): 872-80, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20433879

RESUMEN

We have recently shown that the inhibition of histone deacetylases (HDAC) protects the heart against ischemia and reperfusion (I/R) injury. The mechanism by which HDAC inhibition induces cardioprotection remains unknown. We sought to investigate whether the genetic disruption of gp-91, a subunit of NADPH-oxidase, would mitigate cardioprotection of HDAC inhibition. Wild-type and gp-91(-)(/-) mice were treated with a potent inhibitor of HDACs, trichostatin A (TSA, 0.1 mg/kg, i.p.). Twenty-four hours later, the perfused hearts were subjected to 30 min of ischemia and 30 min of reperfusion. HDAC inhibition in wild-type mice produced marked improvements in ventricular functional recovery and the reduction of infarct size. TSA-induced cardioprotection was eliminated with genetic deletion of gp91. Notably, Western blot and immunostaining displayed a significant increase in gp-91 in myocardium following HDAC inhibition, which resulted in a mildly subsequent increase in the production of reactive oxygen species (ROS). The pre-treatment of H9c2 cardiomyoblasts with TSA (50 nmol/l) decreased cell necrosis and increased viability in response to simulated ischemia (SI), which was abrogated by the transfection of cells with gp-91 siRNA, but not by scrambled siRNA. Furthermore, treatment of PLB-985 gp91(+/+) cells with TSA increased the resistance to SI, which also diminished with genetic disruption of gp91 in gp91(phox)-deficient PLB-985 cells. TSA treatment inhibited the increased active caspase-3 in H9c2 cardiomyoblasts and PLB-985 gp91(+/+) cells exposed to SI, which were prevented by knockdown of gp-91 by siRNA. These results suggest that a cascade consisting of gp-91 and HDAC inhibition plays an essential role in orchestrating the cardioprotective effect.


Asunto(s)
Cardiotónicos/metabolismo , Histona Desacetilasas/metabolismo , Glicoproteínas de Membrana/metabolismo , Miocardio/metabolismo , NADPH Oxidasas/metabolismo , Animales , Apoptosis/fisiología , Supervivencia Celular , Corazón/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/genética , Ácidos Hidroxámicos/farmacología , Masculino , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , NADPH Oxidasa 2 , NADPH Oxidasas/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Distribución Aleatoria , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología
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